The long-term goals of this proposal are to define mechanisms of regulation of hepatic lipase (HL) levels in humans and to determine how genetic variation at the HL gene locus modulates these levels under a variety of physiological and pathological states. HL plays a key role in lipoprotein metabolism by catalyzing the hydrolysis of triglycerides and phospholipids. A high level of HL is associated with two important metabolic risk factors for atherosclerosis: diminished concentrations of plasma high density lipoprotein cholesterol (HDLC) and an increased prevalence of small, dense low density lipoprotein (LDL) particles. Various studies, including those of our group, have shown that a significant proportion (20-25%) of the variability in HL activity is explained by a common genetic variation in the regulatory sequences of the HL gene, and that ethnic/racial background, gender and intraabdominal fat accumulation are other important modulating factors. The underlying hypotheses of this proposal are: first, that additional variants in the HL gene are responsible for variation in HL activity and the associated lipoprotein profiles in different ethnic/racial groups. Second, that high hepatic lipase activity is a risk for the development of cardiovascular disease. Third, that transcription factors whose activity is modulated by ligands would be excellent targets for drug design. Fourth, that HL activity is modulated by the commonly used drugs that modulated lipids. Our preliminary results support these hypotheses. The specific aims are to: 1) Identify a small set of genetic markers that would predict levels of HL activity and the associated lipoprotein phenotypes. 2) Define all hepatic lipase gene variants that are associated with risk for cardiovascular disease. 3) Identify and characterize transcription factors that regulate hepatic lipase gene expression. 4) Determine in human subjects the impact of perturbation of lipid metabolism and insulin resistance on HL activity. The results of these studies will provide insights into the metabolic and molecular bases of interindividual variation in HL activity and the associated plasma lipoprotein profiles. Key transcription factors that regulate HL activity could serve as targets for novel pharmaceutical for inducing a favorable lipoprotein profile. The genetic markers would be valuable in predicting cardiovascular risk as well as response to therapy.